The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 1 2-7
Copyright © 2008 by The Endocrine Society
Approach to the Prostate Cancer Patient with Bone Disease
Susan L. Greenspan
University of Pittsburgh School of Medicine, Clinical and Translational Research Center, Osteoporosis Prevention and Treatment Center, Pittsburgh, Pennsylvania 15213
Address all correspondence and requests for reprints to: Susan L. Greenspan, M.D., University of Pittsburgh School of Medicine, Clinical and Translational Research Center, Osteoporosis Prevention and Treatment Center, 3471 Fifth Avenue, Pittsburgh, Pennsylvania 15213. E-mail: greenspans{at}dom.pitt.edu.
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Abstract
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Prostate cancer is the most common visceral malignancy in men. Androgen deprivation therapy (ADT) is commonly used in patients with nonmetastatic prostate cancer and is associated with significant bone loss and fractures. The greatest bone loss occurs during initiation of ADT. Men should have assessment of skeletal integrity with bone mineral density examination by dual x-ray absorptiometry of the hip and spine. Men with fragility fractures or osteoporosis by bone density should be considered for bisphosphonate therapy. Men with low bone mass may need antiresorptive therapy, depending on other risk factors. Men with a normal bone mineral density should be followed up closely with bone densitometry while on ADT. All men should receive preventive measures with calcium (1200 mg daily in divided doses), vitamin D (800–1000 IU/d), and weight-bearing exercise. Men should be evaluated for additional secondary causes of bone loss including vitamin D insufficiency. Guidelines are needed for androgen-induced bone loss screening and treatment.
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Introduction
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A 74-yr-old man presents to his primary care physician for follow-up after initiation of androgen deprivation therapy for prostate cancer after prostatectomy and radiation therapy. He was placed on Leuprolide, a GnRH agonist, 12 months earlier for prevention of recurrence. He complains of fatigue, decreased libido, and hot flashes. He is becoming stooped but denies any back pain and has not fallen. He is lactose intolerant and avoids dairy products. He participates in little exercise and reports that he consumes approximately four to five alcoholic drinks per week but had consumed more in the past. He previously smoked for 30 yr but quit approximately 20 yr ago. His past medical history is significant for hypertension and he is currently maintained on a β-blocker. He has hyperlipidemia for which he is on a statin.
On physical examination he weighs 150 pounds, and he has mild kyphoscoliosis and a height loss of 2.5 in. His muscle tone is poor without localizing neurological signs. His prostate-specific antigen is 0.6 ng/ml, testosterone is 49 ng/dl, free testosterone is 2.2 pg/ml, and TSH is 1.2 IU. A bone mineral density by dual x-ray absorptiometry (DXA) reveals a spine T-score of –2.3 SD, a femoral neck T-score of –2.7 SD, a total hip T-score of –2.5 SD, and a one third distal radius T-score of –2.6 SD.
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Background
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Bone disease in the patient with prostate cancer is best appreciated with an understanding of skeletal health in men. This older man has osteoporosis as classified by a T-score lower than –2.5 SD at the femoral neck, hip, and one third distal radius. Although osteoporosis is more common in postmenopausal women, it is not uncommon in men. Approximately 20% of all men after the age of 50 yr will have an osteoporotic fracture (1). Men account for 29% of fractures and 25% of costs (2). One third of all hip fractures occur in men (1) and the 1-yr mortality is greater in men (37.5%), compared with women (28.2%) (3, 4). In the United States, 6% of men (1 million to 2 million) have osteoporosis and 28% of men (8 million to 13 million) have low bone mass as assessed by bone mineral density (5, 6).
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Protection from Osteoporosis in Men
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Osteoporosis is less common in men because on average peak bone mass is greater in men (7, 8) and bone size of the radius, femoral neck, and vertebrae are greater in men (7). Men do not have a male menopause during which significant amounts ofbone can be lost. Whereas both genders show cortical thinning, on average men show a greater compensatory increase in cross-sectional diameter and greater cross-sectional area than women with age (9, 10), although this is controversial (3). Finally, men have greater muscle mass, possibly have increased activity during childhood, experience fewer falls, and die at an earlier age.
The etiology of male osteoporosis is similar to that in women; however, in approximately 60% of men, a secondary cause of bone loss may be found (Table 1
) (11). The most common causes of secondary bone loss in men include hypogonadism, glucocorticoids, and excess alcohol (6, 12, 13); however, vitamin D deficiency and insufficiency also contribute. The causes of secondary bone loss in our patient included the hypogonadism from androgen deprivation therapy, past history of smoking, alcoholism, limited calcium consumption, and minimal exercise.
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Bone Mineral Density
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The World Health Organization classification for osteoporosis was based on data for postmenopausal Caucasian women using bone mineral density (14, 15). No evidence-based guidelines for classification are available for men; however, the International Society of Clinical Densitometry recommends using a male database and T-score of –2.5 SD or less (bone mineral density that is equal to or lower than –2.5 SD below the normal mean value for young adult men) to classify osteoporosis similar to the World Health Organization classification for women (16). Classification is usually based on the lowest measurement at the spine, total hip, femoral neck, or one third distal radius when assessed by DXA (16). It is not uncommon to observe discordance in the measurements (found in our patient) due to osteoarthritis and osteophyte calcifications, which can falsely elevate the spine measurement. A forearm measurement at the one third distal radius can be useful for classification, which was done in this case. Men with bone mineral density between –1.0 and –2.5 SD below peak bone mass are in the low bone mass or osteopenic range. Those above –1.0 SD are considered normal. There are no official guidelines for screening men for osteoporosis; however, experts suggest screening men over the age of 70 yr, men who are hypogonadal, use glucocorticoids, or consume alcohol or those with a previous fracture (Table 1
). In addition, patients with other known disorders of bone mineral metabolism such as hyperparathyroidism, vitamin D deficiency or insufficiency, renal osteodystrophy, chronic obstructive pulmonary disease (COPD), and malabsorption and patients taking other medications known to cause bone loss such as androgen deprivation therapy should also have skeletal integrity assessed (Table 1) (13).
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Evaluation for Secondary Causes of Bone Loss
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Although hypogonadism from androgen deprivation therapy has contributed to this patient’s poor skeletal health, all men should also have an evaluation to rule out other secondary causes of bone loss, similar to the evaluation in women (17). The evaluation would include checking serum calcium to rule out hyperparathyroidism; alkaline phosphatase to rule out Paget’s disease; 25-hydroxyvitamin D to rule out vitamin D deficiency or insufficiency; serum protein electrophoresis if there is an anemia to exclude myeloma; a 24-h urine calcium (and creatinine) to exclude hypercalciuria, hypocalciuria, or malabsorption; and PTH if the calcium or vitamin D are abnormal. In a man not on androgen deprivation therapy, testosterone should be assessed. A TSH should be checked in patients on thyroid hormone replacement and older patients with any signs or symptoms of hyperthyroidism. Men with height loss of 2.5 in. or more should be evaluated for vertebral fractures (18). This can be assessed with lateral thoracic and lumbar x-rays or vertebral fracture assessment (VFA), a technology that assesses vertebral fracture using DXA-based technology at the point of service of a bone mineral density (19, 20).
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Prostate Cancer and Androgen Deprivation Therapy
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Prostate cancer is the most common visceral cancer in men and the second leading cause of cancer death (21). Treatment with androgen deprivation has become the norm for metastatic disease (22) and nonmetastatic disease to prevent reoccurrence (23, 24, 25). The use of androgen deprivation therapy (ADT) for localized prostate cancer has increased from approximately 3.7% in 1991 to 30.9% in 1999 (26). ADT usually decreases testosterone in approximately 2 wk and decreases tumor size in approximately 80–90% of patients.
ADT does not have a significant impact on serum calcium, 25-hydroxyvitamin D, or PTH, but initiation of ADT is associated with an increase in bone resorption and formation markers (27), similar to what is observed in early postmenopausal women. Androgen deprivation has been associated with bone loss and changes in body composition. In a cross-sectional study in men with prostate cancer, those treated with a GnRH agonist, compared with those treated without, had bone mass 6.5–17% lower at multiple skeletal sites, higher rates of bone turnover, higher total body fat, and lower lean body mass (28). Studies have demonstrated that ADT such as GnRH agonists and orchiectomy cause significant bone loss after 1 yr (23). Whereas orchiectomy has been shown to cause bone loss of up to 10% in 1 yr at the hip, GnRH agonists have shown bone loss of 0.6–6.5% at the hip and 1.9–6.6% at the spine (23). Furthermore, when men with prostate cancer with or without ADT were followed up prospectively over 12 months, investigators observed that the greatest bone loss occurred in men who had been started on androgen deprivation within 6 months (bone loss 4.0% at the spine, 2.5% at the total hip, and 2.0% at the radius), compared with men who had been on chronic ADT (bone loss 2.0% at the radius), healthy controls, or men with prostate cancer not on androgen deprivation (stable bone mass at the spine and hip) (27).
ADT is also associated with an increase in osteoporotic fractures. Townsend et al. (29) examined men who had been treated with a GnRH agonist for prostate cancer for an average duration of 22 months and found that approximately 9% had one or more fractures. A retrospective study that examined more than 50,613 men with a diagnosis of prostate cancer from the Surveillance, Epidemiology, and End Results-Medicare database from 1992 and 1997 showed a significant increase in fracture rates in men on GnRH agonists (19.4% with fractures), compared with those who had no androgen deprivation therapy (12.6% with fractures) (30). The fracture risk increased with the number of doses of GnRH agonist administered. Smith et al. (31) examined long-term GnRH agonist therapy in a retrospective study using Medicare claims involving 3887 men with nonmetastatic prostate cancer who received GnRH therapy between 1992 and 1994, compared with a group of 7774 men who did not receive GnRH therapy. The rate of any clinical fracture was 7.88 per 100 person-yr at risk in men who received GnRH agonist therapy, compared with 6.51 per 100 person-yr in matched controls with a relative risk ratio of 1.21 (P < 0.001). The rate of vertebral and hip fractures were both significantly higher in men who received GnRH agonist therapy (relative risk 1.45 and 1.30, respectively, both P < 0.01).
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Prevention of Bone Loss due to Androgen Deprivation Therapy
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Several studies demonstrated that bisphosphonates prevent bone loss. A study by Smith et al. (32) compared pamidronate 60 mg iv every 12 wk to placebo in an open-label study of 47 men and reported that pamidronate prevented bone loss at the spine and hip. In a multicenter, double-blind, randomized, placebo-controlled trial of 106 men with androgen deprivation therapy-induced bone loss, those who received 4 mg zoledronic acid iv every 3 months had a greater improvement in bone mass, compared with those in the placebo group (33). Lumbar spine bone mineral density increased by 5.6% in the men receiving zoledronic acid and decreased by 2.2% in the men receiving placebo with a difference of 7.8% (95% confidence interval 5.6–10%, P < 0.001). Mean bone mineral density at the total hip also revealed a difference of 4% between the two groups (P < 0.001). An annual dose of iv 4 mg zoledronic acid has also been shown to improve bone mass over 12 months in men with nonmetastatic prostate cancer on ADT (34). In a double-blind, placebo-controlled, single-site, randomized trial of 112 men with nonmetastatic prostate cancer on androgen deprivation therapy, oral 70 mg alendronate once weekly vs. placebo significantly improved bone mass at the spine (5.1% difference) and hip (2.3% difference, both P < 0.001), compared with the placebo group (35). The selective estrogen receptor modulator raloxifene has been shown to prevent GnRH agonist-induced bone loss at the hip in men with prostate cancer over a year in an open-label study in 48 men (36). Finally, there are ongoing trials with examination of an antibody to rank ligand, denosumab, for prevention of bone loss in men on androgen deprivation therapy for nonmetastatic prostate cancer (37).
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Treatment Considerations
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Guidelines currently suggest total daily calcium intake of 1200 mg daily in divided doses for men over the age of 50 yr (Table 2) (38). Experts suggest vitamin D supplementation of 800-1000 IU/d (39). Furthermore, levels of 25-hydroxyvitamin D should be greater than 30 ng/ml (39, 40). Lifestyle considerations such as weight-bearing exercise, elimination of smoking, and modest alcohol intake are suggested. Although there are several similar guidelines for initiation of treatment for postmenopausal women (38, 41), recommendations for initiation of treatment in men are less clear. The International Society of Clinical Densitometry suggests using similar recommendations for men over the age of 50 yr that are currently used for postmenopausal women (16). This would translate to treatment for men with a fragility fracture or osteoporosis by bone densitometry. Men with bone mineral density T-score above –1.5 SD would receive preventive measures. Depending on additional risk factors, men between –1.5 and –2.5 SD may also require therapy. For example, a frail 75-yr-old man on ADT with a T-score of –1.5 SD and additional risk factors (COPD, alcoholism, vitamin D deficiency) may be at a higher risk of fracture than a 55-yr-old man on ADT with no additional risk factors and a T-score of –2.1 SD. Suggested guidelines for screening and treatment for osteoporosis in men with prostate cancer receiving androgen deprivation have been generated from panels of experts (42) or reviews (23, 43, 44, 45) and follow these recommendations in general. An algorithm based on presence of vertebral fractures, height loss, and bone density is shown in Fig. 1. Currently bisphosphonates are the recommended therapy for prevention of bone loss and treatment of osteoporosis in men on androgen deprivation therapy. Current available therapies approved for osteoporosis in men include oral alendronate and risedronate. However, iv pamidronate and zoledronic acid have been suggested by some investigators (42). Follow-up bone mineral density would be assessed in approximately 1–2 yr.
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FIG. 1. Evaluation and management of bone health in men with prostate cancer on or initiating ADT. BMD, Bone mineral density.
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Controversial and Unanswered Questions
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Because studies suggest that the greatest bone loss occurs with initiation of androgen deprivation therapy similar to rapid bone loss during menopause (27), early screening and preventive or therapeutic measures would be suggested (Fig. 1). However, further work on the initiation of bisphosphonate treatment in men starting ADT is needed. A bone mineral density by DXA along with the assessment of other risk factors would aid in discussions regarding bisphosphonate therapy. Calcium supplementation is another area of controversy. Epidemiological studies have suggested that high levels of calcium intake may suppress PTH and ultimately 1,25-dihydroxyvitamin D and associated with increase risk of prostate cancer (46, 47, 48). Daily intakes of 1500 mg/d or less, however, have not been associated with an increased risk of recurrence. Therefore, it would be reasonable to encourage supplementation at amounts of 1200 mg daily in divided doses.
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Back to the Patient
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The risk factors for osteoporosis in our patient include his past history of smoking, alcohol intake, limited calcium intake, little exercise, and 12-month history of hypogonadism from ADT. The bone mineral density measurement at the hip and radial sites classifies him with osteoporosis. This patient’s evaluation included normal levels of calcium, alkaline phosphatase, complete blood count CBC, and low normal 24-h urinary calcium. His 25-hydroxyvitamin D level was 12 ng/ml, consistent with vitamin D insufficiency. He was advised to take 50,000 U vitamin D2 (ergocalciferol) once per week for 3 months and have the serum calcium and 25-hydroxyvitamin D level rechecked in 3 months (40). In addition, because of his height loss of 2.5 in., he had VFA. If this were not available, he would have been referred for lateral thoracic lumbar spine x-rays. The VFA revealed a compression fracture at T12. Like many patients with vertebral fracture, this patient had no knowledge of vertebral fracture except for his loss of height. Two thirds of all vertebral fractures are silent (49) and can be diagnosed only with a vertebral x-ray or VFA. The finding of a vertebral fracture increases his risk for another fracture 2- to 3-fold (49). Because the VFA does not produce a diagnostic image, vertebral x-rays were performed to exclude a pathological fracture from a metastatic lesion.
In addition to the vitamin D supplementation, the patient was urged to increase his calcium supplementation. He was placed on calcium carbonate 600 mg/d in divided doses. When his vitamin D level is greater than 30 ng/ml, he will then be placed on 1000 IU vitamin D3 (cholecalciferol) daily. He was referred to physical therapy for back strengthening and weight-bearing exercises. He was counseled to limit excessive alcohol intake. Finally, he was placed on a once-weekly oral bisphosphonate. His bone mineral density will be rechecked in 1–2 yr.
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Conclusion
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Androgen deprivation therapy-induced bone loss is a common problem in men with prostate cancer. Although official screening and treatment guidelines have not been established in men, it is reasonable to assess bone mineral density at the time of initiation of ADT because bone loss is greatest at the initiation of this therapy. All men should be counseled to consume appropriate intake of calcium and vitamin D and pursue lifestyle changes including weight-bearing exercise and eliminating excessive smoking and alcohol intake. Men who have osteoporosis with fragility fractures or by bone mineral density with T-score of –2.5 SD or lower should receive therapeutic options such as a once-weekly bisphosphonate. Men in the low bone mass range should have an assessment of other risk factors to determine whether antiresorptive bisphosphonate therapy should be initiated. All men with low bone mass or osteoporosis should have an evaluation to rule out additional secondary causes of bone loss such as vitamin D deficiency or insufficiency. Men with height loss of 2.5 in. or more should be evaluated for a vertebral fracture. Men should have a follow-up bone mineral density in approximately 1–2 yr.
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Footnotes
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Disclosure Statement: The author consults and receives grant support from Merck, Proctor & Gamble, and Amgen; is on the speaker bureau for Eli Lilly; and receives grant support from Novartis and Eli Lilly.
Abbreviations: ADT, Androgen deprivation therapy; COPD, chronic obstructive pulmonary disease; DXA, dual x-ray absorptiometry; VFA, vertebral fracture assessment.
Received June 25, 2007.
Accepted October 9, 2007.
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Abstract
Introduction
